This invention relates to the field of allergy vaccines and treatments. More particularly, the invention contemplates a method of delivery of allergens.
An allergy is the result of a powerful immune system reaction against a substance that should normally be inoffensive to the host. A recent survey by the American College of Allergy, Asthma and Immunology (ACAAI) reveals that approximately 38% of the US population suffers from allergies (Immunotherapy Weekly, Nov. 29, 1999). If the ACAAI estimate is correct, at least 85 million Americans have allergies.
Allergies are caused by an imbalance or hypersensitivity of the immune system, leading to a misdirected immune response. An allergic response occurs when the immune system reacts inappropriately to highly specific agents that in most people do not cause an immune response, such as tree and grass pollens, cockroaches, dust mites, animal dander, latex, or honeybee, wasp and fire ant venoms. Other common allergens include foods such as peanuts, tree nuts, milk, fish, shellfish, eggs, soy, wheat, honey, cantaloupe, strawberries and tropical fruits, drugs such as penicillin, anesthetics, serum, some viruses, bacteria and protozoa, and mold. Delayed type hypersensitivity reactions may occur in response to urushiol, an oil found in poison ivy, poison oak and sumac, resulting in a severe itchy rash and formation of oozing blisters.
Allergens are discussed inter alia in the following articles which are incorporated herein by reference: Blaauw P J, Smithuis O L, Elbers A R. The value of an in-hospital insect sting challenge as a criterion for application or omission of venom immunotherapy. J Allergy Clin Immunol. 1996;98:39-47; Bousquet, J, Lockey, R F, Malling, H-J. Allergen immunotherapy: therapeutic vaccines for allergic diseases [WHO Position Paper]. World Health Organization, Allergy. 1998; 53(suppl):12-16; Lack G, Nelson H S, Amran D, et al. Rush immunotherapy results in allergen-specific alterations in lymphocyte function and interferon-xcex3 production in CD4+ T cells. J Allergy Clin Immunol. 1997;99:530-538; Mxc3xcller U. Diagnosis and treatment of insect sting sensitivity. J Asthma Res. 1966;3:331-333; Weber, R W. Immunotherapy with allergens. JAMA. 1997;278:1881-1887.
The first exposure to an effective allergen causes only a mild immune response that sensitizes the immune system to the substance. However, subsequent exposures to the allergen result in allergic symptoms, typically in a dose dependent manner (ie, the allergen must reach a certain threshold), and may cause an increasingly severe response with repeated exposures. Allergic symptoms include itching and swelling of affected tissues, rashes, muscle spasms and other more severe symptoms. See Table 1 below for the Mxc3xcller classification of allergic reactions. The type of symptom depends on the specific allergen, the part of the body where exposure occurs, and the degree of sensitization of the individual. Allergens that are inhaled often cause nasal congestion, itchy nose and throat, and mucus production. In highly allergic individuals or with higher doses of allergen, coughing, wheezing, or similar symptoms occur. In contrast, ingested allergens cause itching of the throat, vomiting, stomach cramps, diarrhea, and skin rashes or shock, in cases of strong sensitivity. Eczema is also associated with allergies; a decrease in allergies results in an improvement of eczema.
The largest numbers of allergy sufferers, about 45 million Americans, are those who are allergic to pollen and are afflicted with airway diseases such as allergic rhinitis, hay fever and asthma. People with seasonal pollen allergies often develop cross-sensitivity to other allergens that are present all year, such as dust mites. People with chronic respiratory allergies often develop asthma, which is the consequence of long-term activation of the allergic/inflammatory response in the respiratory system. The symptoms of asthma include coughing, wheezing, and shortness of breath due to a narrowing of the bronchial passages, excess mucus production and inflammation. Asthma can be disabling and sometimes fatal.
Cockroach allergy is an allergy to the excrement of cockroaches, and is a trigger of asthmatic attacks. Dust mite allergy is an allergy to the excrement of a microscopic organism living in dust found in all dwellings and workplaces, and in virtually all bedding. Dust mites are perhaps the most common cause of perennial allergic rhinitis, producing symptoms similar to pollen allergy and asthma. About half of all allergy sufferers are allergic to dust mites.
Over 10 million Americans are allergic to animals. Household pets are the most common source of such reactions. Many people think the fur of cats and dogs provokes pet allergies. However, the major allergens are proteins secreted by oil glands in the animal""s skin and shed in dander; and in the saliva, which sticks to the fur when the animal licks itself. When the saliva carrying the proteins dries, the proteins float into the air and are inhaled by people. Some rodents, such as guinea pigs and gerbils, have become increasingly popular as household pets. They, too, can cause allergic reactions in some people, as can mice and rats.
Between 6 and 7 million Americans are affected by food allergies. Food allergies are different from food intolerances, since food intolerances do not involve the immune system. Up to 3 million Americans are highly allergic to peanuts and tree nuts. Eight foods account for 90% of food allergies: milk, fish, peanuts, tree nuts, eggs, soy, wheat, and shellfish. In these cases, systemic reactions may be severe, such as onset of allergic shock. To avoid serious consequences including death, people allergic to foods carry strong antihistamines. Even so, treatment or preventative measures for food allergies are often only marginally effective. The primary therapy is simply total avoidance of the specific allergen. Conventional subcutaneous allergy shots are ineffective against food allergies.
Approximately 5 million people in the Unites States are allergic to bee or wasp stings, in many cases with potentially life threatening symptoms. Three out of 5 of allergic people stung will experience a severe reaction if stung again.
In developed countries, the frequency of allergic reactions has increased dramatically in recent years, to the extent that about 20% or more of the population of the United States has allergies to some common substance. Overall, allergic diseases are the 6th leading cause of chronic disease in the United States. Heredity, environmental conditions, type and number of exposures, and various physiological factors such as stress, fatigue and emotional upset can increase the sensitivity of the immune system and predispose a person to allergies.
The reason for the increase in the number of allergy sufferers is currently under intense scientific debate. There are several possible explanations on which most scientists can agree. Air pollution with nitric oxides (NOx) may play a role in the increasing frequency of allergic airway disease. Not only do nitric oxides increase the production of allergenic proteins in pollen, but they also directly damage sensitive cells lining the airway of the throat and lungs. This damage has the effect of allowing more allergens to get into the body through the damaged cells that normally act as a protective lining. The problem is made worse when smog particles become adsorbed to pollen and act as an adjuvant, enhancing the effects of the allergens.
Scientists widely believe that a phenomenon known as cross-reactivity may also be a cause of the increasing allergy problem. Cross-reactivity occurs when a person, exposed to one particular allergen, subsequently has increased sensitization to another, similar kind of allergen. Food allergies are commonly found to be associated with allergic airway diseases. For example, if the pollen of the hazelnut tree is inhaled, a person may develop an allergy to hazelnuts. Cross-reactivity between allergens from pollen and allergens found in foods may in fact be one of the major causes of food allergies in adults.
In addition, scientists are considering that the large-scale vaccination campaigns and wide spread use of antibiotics over the last few decades, which have dramatically reduced the severity of infectious diseases, may also have altered the population""s immune system, making people more susceptible to allergies. While modem medicine and vaccines have lessened the burden of infectious disease, a possible trade-off may be the increased prevalence of allergies.
In light of the escalating social and economic impact of allergies, tackling allergic diseases has become a medical undertaking of growing importance. Doctors use three general approaches to help people with allergies: they advise patients on ways to avoid the allergen as much as possible, prescribe medication to relieve allergic symptoms, and administer a series of allergy shots. Several potent anti-allergy drugs exist today. However, these drugs merely treat the symptoms of allergies, and some of them carry the risk of serious side effects. Another strategy is to develop ways of conditioning the immune system to respond xe2x80x9cappropriatelyxe2x80x9d to allergens. Only this last approach, allergy shots or immunotherapy, is a causative treatment for allergies.
Allergen immunotherapy or hyposensitization is the practice of administering gradually increasing quantities of an allergen to an allergic subject to ameliorate the symptoms (allergic reaction) associated with subsequent exposure to the causative allergen. Allergen immunotherapy was introduced in 1911 to treat xe2x80x9cpollinosisxe2x80x9d and is currently established as the preferred treatment in the case of severe allergies.
Allergy shots have proven useful in many cases to significantly and permanently relieve the extent of suffering experienced by allergic individuals. In fact, the current allergy shot approach is the only method that may be regarded as a curative means to reverse this disease condition. Early desensitization using the allergy shot approach to specific allergens has also proven somewhat effective against the occurrence of cross-reactive allergies to other substances. For example, a patient receiving allergy shots to treat hay fever by desensitizing against pollen has a decreased risk of becoming allergic to cat hair or other common allergens.
Although allergy shots are currently the only means for treating the disease rather than the symptoms, there are obvious disadvantages to this treatment as it is performed today. Conventional immunotherapy is lengthy, lasting from 2 to 5 years, expensive, and only marginally effective. This treatment is ineffective in one-third of all allergy sufferers and only temporarily effective in one-third of allergic individuals. Immunotherapy has long term effectiveness in only the remaining third of the allergic population.
The treatment duration for conventional immunotherapy is long and time consuming, usually comprising a total of 30 to 100 allergen injections, each requiring 1 hour or more of strict medical supervision after the shot is administered. For desensitization to certain allergens which are known to cause severe side effects, such as insect venom cat hair or dust mites, patients must remain in the doctor""s office for an hour after each injection for observation. Thus, medical and economic costs are very high for this type of treatment.
Allergy shot regimens typically involve 2 treatment phases. The 1st phase employs about 20 allergy shots. During this phase the amount of allergen injected is increased with each dose, starting with minute amounts (as low as 0.01 xcexcg). Injections of diluted extracts of the allergen are administered on a regular schedule, usually twice a week or weekly at first, in increasing doses until a maintenance dose of about 100 xcexcg has been reached. This maintenance dose, reached after about 20 weeks, is then injected every 2 to 4 weeks for a period of 3 or more years.
It usually takes several months and may take up to 3 years to reach a maintenance dose. Patients may experience some relief within 6 months; however, if there is no benefit within 18 months, the shots are generally discontinued. After stopping immunotherapy, about one-third of allergy sufferers no longer have any symptoms, one-third have reduced symptoms, and one-third relapse completely.
In addition, during the desensitization phase, as more allergen is administered the injections usually cause moderate and sometimes severe side effects ranging from soreness and local swelling (wheal) or rash (flare) at the injection site to systemic allergic effects such as generalized skin rash or hives (urticaria), asthma, or even allergic shock (anaphylaxis). Other common side effects of immunotherapy include general itching (pruritis), red eyes and low blood pressure. Side effects usually occur within 20 minutes, although some can develop up to 2 hours after the allergy shot is given. Anaphylaxis refers to an allergic reaction characterized by a sharp drop in blood pressure, hives or welts, and breathing difficulties, that occurs immediately, progresses rapidly and is life-threatening. Anaphylaxis is the most severe reaction that can result from standard immunotherapy.
Development of a specific immune response requires that the cells of the immune system encounter an antigen, and that T and B lymphocytes interact with each other and with other antigen presenting cells (APC) to eliminate extracellular pathogens or toxins. When an allergic person first comes into contact with an allergen, the immune system generates large amounts of a type of antibody called immunoglobin E, or IgE. Each IgE antibody binds with high affinity to one particular allergenic substance. In the case of pollen allergy, the antibody is specific for each type of pollen. For example, one type of antibody is produced to react against mugwort pollen, and another against ragweed pollen. Bee venom, which contains the protein PLA2, elicits anti-PLA2 antibodies. During the initial phase of the immune response, low-affinity anti-PLA2-specific IgG1 antibodies are generated. After repeated stings, patients with normal immunity develop high-affinity anti-PLA2-specific IgG4 antibodies, but patients allergic to bee venom develop anti-PLA2-specific IgE antibodies. Immune-stimulating mast cells in tissue, and basophils in blood will bind to the IgE antibody and release powerful inflammatory mediators (cytokines). These cytokines act on tissues in various parts of the body, such as the respiratory system, causing the symptoms of allergy.
Successful immunotherapy is accompanied by a decrease in PLA2-specific IgE, and an increase in PLA2-specific IgG. The precise mechanisms by which allergen immunotherapy achieves clinical improvement in the symptoms of allergic patients is still not completely clear, but it seems as though IgG antibodies may protect against allergic reaction. Immunotherapy is associated with a reduction in allergen-induced IL-4 and IL-5 cytokine secretion, and a simultaneous increase in IFN-xcex3 secretion by allergen-specific T cells.
It is one object of the present invention to provide an effective method of delivery of allergens.
It is a further object of the invention to provide a method of delivery of allergens which effectively employs a low dosage of allergens.
It is a still further object of the invention to provide a regimen of treatment for allergies which is effective to modulate an allergic condition after only a few injections.
It is an additional object of the invention to provide a mode of treatment with allergens which is characterized by reduced adverse side effects.
This invention contemplates a method of modulating an allergic response of an individual comprising delivery by direct injection of an allergen to a lymph node of said individual whereby the allergic response is modulated. For individuals who lack lymph nodes or who possess defective lymph nodes, the allergen may be delivered to the lymphatic tissue or to an immune cell. In one specific aspect of the invention the allergen is delivered in combination with an adjuvant, or is precipitated on, or bound to a delivery or formulation substance. Still other aspects of the invention are described in the Description of the Preferred Embodiments of the Invention.
This invention contemplates using intranodal delivery of allergens to re-equilibrate the immune system more effectively than can be accomplished utilizing conventional immunotherapy. The invention provides efficient and effective modulation of a wide variety of allergic responses and represents a major improvement over the current approach. For example, using the preferred embodiments, modulation or elimination of an allergic condition can be achieved with as few as 1 to 3 injections. The targeted delivery also allows the use of smaller amounts of allergen than are used in conventional allergy shots, greatly reducing the potential for side effects such as urticaria, dyspnea, syncope, hypotension, myocardial events and even death.